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Direct evidence that sporadic colorectal cancers (CRCs) can arise from an interaction between genes and environment has come from a study of gene variation affecting the power of an enzyme to detoxify known carcinogens.
Identification of genetic polymorphisms of the human UDP-glucuronosyltransferase (UGT)1A7 gene—a new risk factor—may also improve primary prevention of CRCs in some patients. UGT1A7 is crucial in detoxifying environmental mutagens—cyclic aromatic compounds—by the action of its enzymic product.
Two polymorphisms in the UGT1A7 gene in particular were related to CRC. The frequency of wild type alleles UGT1A7*1/1 was much lower in patients with CRCs than controls (9% v 20%; odds ratio 0.39 (95% confidence interval 0.17 to 0.92)). The frequency of polymorphic alleles was significantly higher in patients than controls for UGT1A7*3/1 (19% v 10%; 2.26 (1.09 to 4.68)), UGT1A7*3/2 (19% v 9%; 2.39 (1.15 to 4.99)), and for UGT1A7*3 alleles combined (50% v 27%; 2.75 (1.6 to 4.71)). CRCs were also significantly associated with UGT1A7 polymorphisms —especially UGT1A7*3—when tested by logistic regression.
The activity of each of these UGT1A7 polymorphisms in detoxifying a range of cyclic compounds in vitro was much lower than that of the wild type genotype, and UGTA17*3 polymorphisms had no detectable activity.
The study included 210 healthy blood donors as controls and 78 patients with CRCs. UGT1A7 genotypes were determined by PCR and sequence analysis of DNA extracted from blood samples. Enzyme activity was assayed with a human cell line transfected with plasmids containing polymorphic variant DNA.